Study of efficacy and safety of asciminib in addition to imatinib in CML-CP patients without a deep level or response on imatinib

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

26 Nov 2018 → 27 Feb 2025

Decision date (initial)

2024-10-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Novartis Pharma Services AG

External identifiers

EU CT number

2024-515040-23-00

EudraCT number

2018-001594-24

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacokinetic

The primary objective of this study is to assess whether asciminib 40 mg once daily (QD) + imatinib 400 mg QD or asciminib 60 mg QD + imatinib 400 mg QD is more effective than continued imatinib by testing the MR4.5 rate at 48 weeks.

Secondary objectives 6

1. To estimate efficacy of switch to nilotinib assessed by the MR4.5 rate at 48 weeks.
2. To estimate difference in efficacy between asciminib 60 mg + imatinib and switch to nilotinib considering the difference in MR4.5 rate at 48 weeks.
3. To estimate difference in efficacy between asciminib 40 mg + imatinib and switch to nilotinib considering the difference in MR4.5 rate at 48 weeks.
4. To assess additional parameters of the efficacy of asciminib 60 mg or 40 mg added to imatinib versus continued imatinib or switch to nilotinib i.e. the rate of MR4.5 at 96 weeks, rate of MR4.5 by 48 and 96 weeks, sustained MR4.5 at 96 weeks and time to MR4.5.
5. To characterize the safety and tolerability profile of asciminib 60 mg or 40 mg + imatinib versus continued imatinib or switch to nilotinib by comparing the incidence and severity of adverse events (AEs), changes in laboratory values, clinically notable ECG abnormalities and vital signs.
6. To assess the pharmacokinetic profile of asciminib 60 mg or 40 mg and imatinib when administered in combination.

Conditions and MedDRA coding

Chronic Myelogenous Leukemia in chronic phase (CML-CP), previously treated with imatinib and have not achieved deep molecular response

Regulatory references

Plan to share IPD

No

IPD plan description

Not available

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Signed informed consent must be obtained prior to participation in the study.
2. Male or female patients ≥ 18 years of age with a confirmed diagnosis of CMLCP.
3. Minimum of one year (12 calendar months) treatment with imatinib first line for CML-CP (patients have to be on imatinib 300 mg QD or higher).
4. BCR-ABL1 levels > 0.01% IS and ≤ 1% IS at the time of study entry as confirmed with a central assessment at screening; patients must not have achieved deep molecular response (MR4 IS) at any time during prior imatinib treatment.
5. Patient must meet the following laboratory values before randomization: • Absolute Neutrophil Count ≥ 1.5 x 109 L • Platelets ≥ 75 x 109/L • Hemoglobin ≥ 9 g/dL • Serum creatinine (sCr) < 1.5 mg/dL • Total bilirubin (TBL) ≤ 1.5 x upper limit of normal (ULN) except for patients with Gilbert’s syndrome who may only be included with total bilirubin ≤ 3.0 x ULN • Aspartate aminotransaminase (AST) ≤ 3.0 x ULN • Alanine aminotransaminase (ALT) ≤ 3.0 x ULN • Alkaline phosphatase (ALP) ≤ 2.5 x ULN • Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN - ≤ 1.5 x ULN, value must be considered not clinically significant and not associated with risk factors for acute pancreatitis
6. Patients must have the following laboratory values (≥ lower limit of normal (LLN)) or corrected to within normal limits with supplements prior to randomization: • Potassium (potassium increase of up to 6.0 mmol/L is acceptable if associated with creatinine clearance* within normal limits) • Total calcium (corrected for serum albumin); (calcium increase of up to 12.5 mg/dl or 3.1 mmol/L is acceptable if associated with creatinine clearance* within normal limits) • Magnesium (magnesium increase up to 3.0 mg/dL or 1.23 mmol/L if associated with creatinine clearance* within normal limits. *Creatinine clearance as calculated using Cockcroft-Gault formula

Exclusion criteria 7

1. Treatment failure according to ELN 2013 criteria during imatinib treatment.
2. Known second chronic phase of CML after previous progression to accelerated phase/blast crisis (AP/BC).
3. Previous treatment with any TKIs other than imatinib
4. History or current diagnosis of ECG abnormalities indicating significant risk or safety for subjects participating in the study such as: • History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to randomization • Concomitant clinically significant arrhythmias, e.g. sustained ventricular tachycardia, and clinically significant second or third degree atrioventricular (AV) block without a pacemaker • Resting QTcF ≥ 450 msec (male) or ≥ 460 msec (female) prior to randomization • Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following • Risk factors for Torsades de Pointes including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia • Concomitant medications with a "known" risk of Torsades de Pointes per qtdrugs.org that cannot be discontinued or replaced by safe alternative medication • inability to determine the QTcF interval
5. Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. uncontrolled diabetes, active or uncontrolled infection, uncontrolled clinically significant hyperlipidemia and high serum amylase).
6. History of acute pancreatitis within 1 year prior to randomization or past medical history of chronic pancreatitis or history of acute or chronic liver disease.
7. History of other active malignancy within 3 years prior to randomization with the exception of basal cell skin cancer, indolent prostate cancer and carcinoma in situ treated curatively.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Molecular Response (MR)4.5 rate at 48 weeks

Secondary endpoints 4

1. • Molecular Response (MR)4.5 rate at 48 weeks • Difference in rate of MR4.5 at 48 weeks
2. • Rate of MR4.5 at 96 weeks • Rate of MR4.5 by 48 and 96 weeks • Sustained MR4.5 at 96 weeks • Time to MR4.5
3. Incidence and severity of adverse events, changes in laboratory values, clinically notable ECG abnormalities and vital signs
4. Plasma concentrations of asciminib and imatinib when administered in combination. PK parameters include but are not limited to Cmax, Tmax, Cmin, AUClast and AUCtau

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 9

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 15

Locations

5 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 67 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications